Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients

Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients Anne Morice, Maxime Taverne, Sophie Eché, Lucie Griffon, Brigitte Fauroux, and 7 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-1574137/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 18 Apr, 2023 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted 4 You are reading this latest preprint version Abstract Background Achondroplasia is the most frequent FGFR3-related chondrodysplasia, leading to rhizomelic dwarfism, craniofacial anomalies, stenosis of the foramen magnum, and sleep apnea. Craniofacial growth and its correlation with obstructive sleep apnea syndrome has not been assessed in achondroplasia. In this study, we provide a multimodal analysis of craniofacial growth and anatomo-functional correlations between craniofacial features and the severity of obstructive sleep apnea syndrome. Methods A multimodal study was performed based on a paediatric cohort of 15 achondroplasia patients, including clinical and sleep study data, 2D cephalometrics, and 3D geometric morphometry analyses. Results Craniofacial phenotype was characterized by maxillo-zygomatic retrusion, deep nasal root, and prominent forehead. 2D cephalometric studies showed constant maxillo-mandibular retrusion, with excessive vertical dimensions of the lower third of the face, and modifications of cranial base angles. All patients with available CT-scan had premature fusion of skull base synchondroses. 3D morphometric analyses showed an aggravation of the craniofacial phenotype with age, predominantly affecting the midface - with increasing maxillary retrusion with age - as well as the skull base - with closure of the spheno-occipital angle. At mandibular level, both mandibular corpus and ramus showed significant levels of shape modifications with age, the highest level concerned the mandibular corpus (+119%). Anatomo-functional studies revealed significant correlation between the severity of maxillo-mandibular retrusion and obstructive sleep apnea syndrome (p<0.01). Conclusions Our study provides new insights on the impact of FGFR3 activating mutations on craniofacial growth, and highlights anatomo-functional correlation between the severity of craniofacial features and obstructive sleep apnea syndrome. Achondroplasia FGFR3 sleep apnoea geometric morphometrics cephalometrics principal component analysis craniofacial growth Figures Figure 1 Figure 2 Figure 3 Figure 4 Figure 5 Background Achondroplasia (ACH, OMIM 100800) is the most frequent form of chondrodysplasia, occurring with an incidence ranging from 1/30 000 to 1/10 000 1,2 . Clinical presentation is characterized by rhizomelic dwarfism and craniofacial anomalies, including macrocephaly, frontal bossing, midface retrusion, mandibular malformations, and cranio-vertebral junction anomalies 1 – 4 . Achondroplasia is due to activating mutations in the Fibroblast Growth Factor Receptor 3 gene ( FGFR3 ), consisting in a glycine -to- arginine substitution in the transmembrane domain of the receptor (position 380) in more than 97% of cases 5 , 6 . Activating FGFR3 mutations lead to disorganisation of growth plate cartilage, premature fusion of the skull base synchondroses and impairment of the bone elongation 3,7−10 . Today, the exact function of FGFR3 activating mutations on craniofacial skeletal phenotype and growth in ACH is not well understood. A better characterization of skull bone anomalies using 3D representation is needed to better understand the multiple craniofacial anomalies. In clinical practice, describing growth and form of the skull in ACH is crucial to evaluate the functional consequences of midfacial retrusion, mandibular malformations, to establish evidence-based treatment plans. Obstructive and central sleep apnea are among the most critical functional issues in ACH, affecting 60% of patients 11 , 12 , and have been related to a sagittal shortening of the cranial base and stenosis of the foramen magnum 13 . This obstructive sleep apnea (OSA) 14 is partially due to midfacial retrusion. Currently, the relationship between skeletal craniofacial shape and functional respiratory anomalies is not well understood. Deciphering the craniofacial morphology and its growth in patient with ACH could help assess the beneficial effects of promising medical treatments that are currently being developed to counteract the effects of activating FGFR3 mutations 15 , 16 . The aim of this study was to better characterise and quantify the skeletal craniofacial phenotype in a cohort of 15 ACH patients, using clinical evaluation, 2D cephalometrics and 3D geometric morphometrics. We also investigated the relationship between craniofacial shape and sleep study parameters, to understand whether craniofacial anomalies could be predictive of the severity of obstructive sleep apnea. Methods Patients All ACH patients were initially managed in the National Reference Centres for Congenital Bone Diseases (Centre de Référence Maladies Rares MOC) and for Cleft and Maxillofacial Malformations (Centre de Référence Maladies Rares MAFACE), located within Necker hospital. This retrospective study included ACH patients from 2017 to 2021 with confirmed FGFR3 gain of function mutation. We analysed clinical and orthodontics evaluation and photographs, respiratory polygraphic (PG) results, lateral cephalograms, and craniofacial computed tomographic (CT) scans, being both performed before any skeletal craniofacial procedure. Patients whose ages at PG and at cephalograms were not similar (> 20% of difference), were excluded from the study. To account for facial characteristics and to screen for potential clinical predictive factors of OSA, we classified three morphological features - maxillo-zygomatic retrusion, deep nasal root, prominent forehead - into three grades of severity. Facial profile was classified into three types (convex, concave, or flat) (Fig. 1 ). Occlusion was defined using the Angle classification 26 . Controls Controls were selected among age and gender-matched patients without any reported craniofacial anomalies. These patients underwent CT-scans for the assessment of benign craniofacial trauma or infections (lower jaw infections excluded). Cephalometric analysis Cephalometric analysis was performed according to Delaire's principles 17 , using lateral cephalograms, with the software DELAIRE CEPHALOMETRIE (Blued'IS, Béthemont la Forêt, France). Fourteen landmarks were manually placed on each lateral cephalogram, defining 12 lines. Cranial and facial cephalometric analyses are described in supplementary data section (Figure S1 and Table S1). Investigation of skull and mandible shape An initial macroscopic analysis aimed at detecting potential premature fusion of skull vault sutures and skull base synchondroses, graded as follows: grade 1 (open), grade 2 (partially closed), and grade 3 (completely closed) 18 – 20 . Twenty landmarks were placed on the skull and twenty-three landmarks were placed on the mandible (Fig. 2 , Table S2) using Avizo 2020 (Thermo Fisher Scientific). All computations and statistical analyses were performed using R 21 . Landmarks were aligned using Procrustes superimposition ( procSym , Morpho package) 22 , either with (1) standardisation of overall size (generating Procrustes coordinates), and (2) without scaling (generating Boas coordinates). With and without scaling, the 3D coordinates of the aligned points were combined into matrices to perform subsequent multivariate statistical analyses. All following analyses that generated theoretical 3D shapes used the mandible and the skull of a control individual as the reference shape. This reference shape was obtained by segmenting the CT-scan images of the individual with Avizo and by exporting the constructed volumes as 3D surface objects. Growth trajectories within each group of subjects were estimated from two-blocks partial least-squares regressions (2b-PLS), using pls2B from the Morpho package 22 . The first block corresponded to the Procrustes or Boas coordinates, and the second block corresponded to the log10-transformed age in years. Theoretical morphological variations along the statistically significant axis of covariation between shape and age were displayed using tps3d ( Morpho package) 22 . Patterns of morphological changes during growth were compared between groups of individuals, first qualitatively, then quantitatively using the compare.pls ( geomorph package) 23 – 25 . The covariation axes of the 2b-PLS regressions of Procrustes coordinates relative to age were used to extract theoretical morphologies at 6 different ages in each group: 0.5, 1, 3, 6, 9 and 12 years of age. Procrustes distances were computed for each landmark between the theoretical shapes in the two groups of patients, to estimate possible aggravation, defined as the increase in morphological differences between controls and patients with age. Deformation was then averaged within subsets of landmarks corresponding to 5 anatomical regions (Fig. 2 ). For the skull, three areas were considered: the face (LM 1–13), cranial vault (LM 14–17), and skull base (LM 18–20). For the mandible, we considered two areas: the mandibular ramus (LM 1–5, 11–19, 22) and mandibular corpus (the remaining landmarks). For each of these 5 anatomical regions, a logarithmic equation describing the evolution of deformation with age was generated. These growth equations enabled predicting deformation with age. The relationship between the intensity of morphological deformation and indices of apnea (see below, apnea-hypopnea index = AHI and obstructive AHI = OAHI) was investigated by computing stepwise regressions (using stepAIC from the MASS package) 26 between AHI or OAHI and the deformation of the five previously defined anatomical areas. Sleep parameters Overnight PG with the recording of nasal flow, respiratory movements (bands), tracheal sound, body position, electrocardiogram, heart rate, pulse oximetry (SpO 2 ), and transcutaneous carbon dioxide pressure (PtcCO2) were performed in room air (American Thoracic Society, 1996). Obstructive, central, mixed apnea and hypopnea were defined as previously described 11 , 12 . The AHI was calculated as the sum of the apnea and hypopnea events per hour of total sleep. Sleep study was considered normal for AHI 5 /hour. All available PG from all patients were considered to evaluate the evolution of sleep apnea during growth and after airways surgery. Relationships between cephalometric and sleep parameters The correlation between each quantitative sleep parameter individually and all cephalometric variables was investigated through stepwise multiple regressions (using step.AIC from the MASS package. This enabled the best model to be retained by minimising the Akaike Information Criterion (AIC). Hence, the relative contributions of the explanatory variables to the variation of the dependent variable were assessed by computing the standardised (beta) coefficients. Non-parametric three-way multivariate analyses of variance (MANOVAs with permutation procedure) enabled the estimation of the effects of the severity of maxillo-zygomatic retrusion, age and sex on the cephalometric and sleep parameters, using procD.lm from the geomorph package. Univariate pairwise permutation tests (alternative to the parametric univariate analyses of variance - ANOVA - and to post-hoc tests) were computed with pairwise PermutationTest from the rcompanion package 28 . These analyses aimed to investigate the effect of the factors that had shown significant influence in earlier multivariate analyses on individual cephalometric variables separately, and to perform pairwise mean comparison. The procedure applied a Bonferroni adjustment of the p-value to balance the biases of multiple comparisons. Results Patients Fifteen ACH patients were included. Mean age at initial clinical evaluation was 7.8 ± 3.3 years; female / male ratio was 5/10. Genetic studies revealed the presence of a G380R mutation in FGFR3 gene in all tested patients (n = 13). In the two remaining patients, born more than 15 years before the time of the study, molecular screening had not been performed, as genetic molecular confirmation was not mandatory at this period in these cases of typical clinical presentation of ACH. All patients presented a severe rhizomelic dwarfism, characterized by short limbs and trunk. Craniofacial morphological multimodal assessment Clinical assessment Four patients presented i) mild, eight ii) moderate and three iii) severe maxillo-zygomatic retrusion (Fig. 1 ). Nasal root was deeply depressed in eleven patients and was less depressed in four patients. Forehead was flattened in 3/15, otherwise moderate convexity or marked prominent forehead affected 7/15 and 5/15 patients respectively. Profile was concave in 10/15, flat in 4/15, and convex in 1/15 patients. Cephalometric analysis Mean age at cephalometric analysis was 7.9 ± 3.2 years and was not statistically different from mean age at clinical evaluation. Maxillary retrusion and retrognathism, in relation to cranio-adapted F1, affected all patients (n = 15). Skeletal Angle class was predominantly type III (n = 10/15), and less frequently I or II (n = 3 and 2/15, respectively). Gonial angle was mostly obtuse (n = 13) (relative to F3/F7 angle) and acute in 2/15 patients. All patients had excessive vertical dimension of the lower third of the face. Cranial base angles were abnormal in all patients, the anterior angle being obtuse (> 22°) in 8/15 patients, and the posterior angle acute (< 115°) in 13/15 (Table 1 ), accounting for modifications of the cranial base shape due to premature fusion of the skull base synchondroses (see below). Table 1 Cephalometric analyses (n = 15 patients). SD: standard deviation. For the definition of the cephalometric parameters (C1, F1, F1M, F1m, C2, C4), see Fig. 1 / Suppl Table 1. Mean ± SD Definition Age (years) 7.9 ± 3.2 C1/F1 angle (degrees) 87.8 ± 5.3 Maxillo-mandibular position Maxillary position C1/f1M angle (relative to F1) − 10.3 ± 4.9 maxillary retrusion (n = 15) Mandibular position (C1/f1m angle) (relative to F1) − 8 ± 4.3 retrognathism (n = 15) Maxillo-mandibular discordance (f1M/1m angle) − 2.2 ± 4.4 Angle class I/II/III (n = 3/2/10) Gonial angle (degrees) 129.6 ± 20.32 open n = 13, closed n = 2 (relative to F3^F7 angle) Vertical excess of the lower third of the face (%) + 6 ± 0.02 lower facial excess (n = 15) Cranial base angles (degrees) C1/C2 angle 23.8 ± 4.53 (20–22) anterior angle of the cranial base (open n = 8, closed n = 5, normal n = 1) C1/C4 angle 111.2 ± 11.3 (115–120) posterior angle of the cranial base (open n = 1, closed n = 13, normal n = 1) Craniofacial shape and growth: 3D-CT assessment Cranial sutures and skull base synchondroses Craniofacial CT-scans were available for 11/15 patients (female/male ratio: 3/8), with a mean age of 4.9 ± 4.9 years (range 0,2–13.6). Premature fusion of the squamo-sphenoidal suture affected 8/11 patients: either in a partial or complete form (4 patients each). A large anterior fontanelle was observed in 5/11 patients (all aged under 2 years), and 2/11 patients presented a mild fontanelle closure delay (ages 2.6 and 2.8 years). All 11/15 patients presented with premature fusions (1) of the intra-sphenoidal synchondrosis (ISS) with 10/11 in a complete form (grade 3) and in 1/11 a partial form (grade 2); (2) of the spheno-occipital synchondrosis (SOS) with 9/11 in a complete (grade 3) and 2/11 in a partial form (grade 2), and (3) of the intra-occipital synchondrosis (IOS) bilaterally with 8/11 in a complete form (grade 3) and 3/11 in a partial form (grade 3). A complete fusion of the spheno-ethmoidal synchondrosis (grade 3) was observed in 7/11 patients, though it remained open (grade 1) in 4/11 patients. Growth trajectories Both standardized (Procrustes coordinates) and non-standardized (Boas coordinates) skull and mandible shapes strongly covaried (rPLS > 0.9) with age within the ACH group and the control group (Table S3, Fig. 3 ). The strength of the covariation, provided by the rPLS index, was never significantly different between the two groups of patients, suggesting that intra-group variability in phenotype relative to age was comparable in the two cohorts. The 2b-PLS regressions between Boas coordinates of the skull and age showed that, compared with controls, the growth of the skull in ACH was characterized by an overall retrusion of the midface and a forward tilting of the anterior aspect of the skull base, leading to a tightening of the space between skull base and the posterior part of the maxilla (Fig. 3 ). More precisely, facial shape in ACH was characterised by a deep nasal root and a maxillo-zygomatic retrusion. The angulation of the skull base at the site of the SOS (with subsequent forward and downward tilting of the basisphenoid) and reduction of the skull base antero-posterior dimensions were associated with a shortening of the skull length. The orbits were vertically more elongated than in the control group. The skull vault became higher with age in the frontal region (which is mostly described by cephalometric landmark FPmid (Figs. 2 and 3 and Table S2), compared with controls. Growth anomalies were also highlighted by 2b-PLS regressions between Procrustes skull coordinates and age, suggesting that these were not only due to size, but rather corresponded to disease-specific phenomena. The 2b-PLS regressions between Boas coordinates of the mandible and age showed that mandible growth in ACH was characterized by a backwards shift of the symphysis and greater symphysis height (defined as the distance between cephalometric landmarks 8 Pog and InfDe, see Figs. 2 , 3 and Table S2). Additionally, the mandibular ramus became narrower and more vertical overall, the notch of the sigmoid was more profound, the coronoid process and the condyle were more vertically positioned, and the segment between the retromolar region and the mandibular ramus was more concave. A decrease in the overall antero-posterior length of the mandible seemed to occur before teenage years, characterized by the shortening and verticalization of the condyle in older ACH patients. This decrease in length did not seem to occur in the first years of life. Similar results were obtained after scaling, suggesting that size moderately affected these morphological variations. Phenotypic aggravation with age Skull vault showed the highest level of deformation between controls and patients (Fig. 4 ). Skull height increase was one of the main features of ACH. Nevertheless, the skull base and the face showed the most significant levels of aggravation with age (approximately + 75% to + 106% of phenotypic deformation from 6 months to 12 years old, respectively) (Table S4). The facial landmarks that showed the greatest aggravation with age were those surrounding the nostrils (InfExOL, InfNasApR, InfNasApL, InfNasMid, Fig. 2 , Table S4). Both the mandibular ramus and corpus showed comparable levels of phenotypic deformation between controls and patients. The most pronounced levels of aggravation were in the mandibular corpus (+ 119% of phenotypic deformation). When considering landmarks separately and not by anatomical region, it appeared that not all landmarks showed the same levels of aggravation with age. Overall, disparity in the levels of aggravation among landmarks increased with age (Fig. 4 ). Within the mandibular ramus, the areas experiencing the greatest deformation were the coronoid process, the condyle and the gonion (CorR, CoExtR, GoR, CorL, CoExtL, GoL); and within the mandibular corpus, the most inferior part of the chin (MeR, MeL, Fig. 2 and Table S4). No significant model was retained from the stepwise regressions between the intensity of shape deformation and indices of apnea (all p > 0.05). Functional assessment: obstructive sleep apnea syndrome Polygraphic results and upper airway surgery Mean age at sleep study was 7.8 ± 3.2 years, which was not statistically different from mean age at cephalometric study (difference 0,1491 ± 1,198). Sleep anomalies affected 80% of patients, with 33% patients having severe obstructive sleep apnea syndrome (AHI > = 10 events/hour) (Tables S5 and S6). Abnormal desaturations were observed in 13/15 patients. Apneas were mostly obstructive; the median index of central apnea was 0 (range 0–2.2). In our series, cranio-vertebral decompression had been performed in 4/15 patients with central apnea due to foramen magnum stenosis. In these cases, sleep analyses selected for the present study were performed after cranio-vertebral decompression. Fourteen out of 15 patients benefited from upper airways surgery, mostly adeno-tonsillectomy and turbinectomy (Table S5). One out of 15 patients with severe ventilation disorders of multiple origins (pulmonary hypoplasia, obstructive apnea and central apnea due to upper spinal cord compression) had a tracheostomy and a cranio-vertebral decompression at the age of one and was decannulated two weeks post-operatively. Six out of 15 patients benefited from non-invasive continuous positive airway pressure (CPAP) ventilation, starting at the mean age of 4.9 ± 3.2 years, and CPAP had been stopped following a normal sleep study without CPAP in 3/6 of them (mean age 9 ± 1.7 years). In average, higher values of AHI and OAHI were observed at the ages 1–3 (19.5 ± 42.1, 13.5 ± 28.9 evens/hour, respectively) and 6–9 years of age (19.1 ± 42.2, 15.2 ± 30.3 events/hour, respectively) than at other ages (Fig. 5 ), although not significantly (p = 0.9, Kruskal-Wallis’s test). Craniofacial phenotype and sleep disorders: anatomo-functional correlation Stepwise regressions between each sleep parameter and the set of cephalometric variables retained three statistically significant models (Table S7). Greater AHI and OAHI values were both associated with more pronounced maxillary retrusion and retrognathism, and with smaller C1-C2 values. When maxillary and mandibular retrusion increased, SpO2 min decreased. Non-parametric MANOVAs with permutation detected no relationship between sleep study parameters and the severity of maxillo-zygomatic retrusion, sex, and age (all p > 0.05, Table S8). Cephalometric parameters were influenced by the grade of maxillo-zygomatic retrusion (p = 0.034; R² = 0.157; F = 2.538; Z = 1.904) and sex (p = 0.011; R² = 0.178; F = 2.874; Z = 2.287). More specifically, the univariate pairwise permutation tests did not reveal any significant relationship between the severity of maxillo-zygomatic retrusion and cephalometric parameters considered separately (Table S9). However, levels of maxillary retrusion and values of C1-C4 angles differed between sexes, with boys presenting with more severe maxillary retrusion and lower C1-C4 angle values than girls. Discussion FGFR3 is involved in craniofacial membranous and endochondral ossification processes 3 , 29 . Gain-of-function FGFR3 mutations lead to dwarfism (ACH, hypochondroplasia, and thanatophoric dysplasia) 5 , 30 , 31 but also craniofacial suture fusions (craniosynostoses: Muenke syndrome and Crouzon syndrome with acanthosis nigricans ) 32 , 33 . Even though all the ACH patients reported here presented typical craniofacial features (frontal bossing, macrocephaly, maxillary retrusion, deep nasal root, and prognathism) 3 , 4 , 34 , we observed three grades of facial phenotype severity – ‘mild’, ‘moderate’ or ‘severe’ –, suggesting a phenotypic disparity in a genetic disease due in > 95% to a same G380R FGFR3 mutation. All patients presented a maxilla and mandible retrusion, an opening of gonial angle, a closure of the posterior skull base angles and a vertically elongated chin, confirming previous findings in ACH 34 , 35 . Our 3D morphometric analyses suggested an aggravation of the craniofacial phenotype with age. The most affected craniofacial region was the midface, characterised by an increased maxillary retrusion and a deeper nasal root with age. Aggravation of midface retrusion is most probably related to the premature fusion of skull base synchondroses consequently to activating FGFR3 mutations that impair cartilage homeostasis 3 , 36 , as observed in ACH mouse models. Normal synchondrosis fusion in humans follows a specific age-related sequence: ISS before the age of 2, IOS before the age of 7, spheno-ethmoidal synchondrosis before the age of 9, and SOS before puberty 20 , 37 , 38 . Premature fusion of skull base synchondroses was always observed in our series, at the site of ISS, SOS and IOS. Gradual premature fusion of skull base synchondroses contributes to anteroposterior facial growth restriction and subsequent maxillary and midfacial retrusion 19 , 20 , 39 . In our series, we observed abnormal angulations at the site of the SOS. These skull angle modifications may be related to the premature fusion of the skull base synchondroses, but we cannot exclude the influence of intrinsic brain anomalies, especially of the temporal region, as already reported in FGFR mutations 40 , 41 . In addition, shape changes of the foramen magnum may also be involved in skull base anomalies, with secondary repercussions on the midface 3 , 42 . Premature fusion of skull vault sutures was observed in 80% of the patients at the squamo-sphenoidal suture, and all patients under the age of 2 had a large anterior fontanelle, indicating potential anomalies in the membranous ossification of the skull vault 3 . In addition, brain anomalies and subsequent intracranial hypertension may also worsen skull shape deformations, fontanelle closure delay and frontal bone ossification delay. However, previous ex vivo studies conducted on a mouse model of ACH, Fgfr3 Y367Y/+ , showed that the ossification delay of skull vault occurred independently of the brain and cranial base, suggesting an intrinsic influence of FGFR3 gain-of-function mutations on membranous ossification 3 . Premature synostosis of one cranial suture constrains cranial growth at the site of the suture, and continuous growth of the underlying brain induces compensatory skull vault growth at the site of other non-fused cranial sutures, leading to skull deformations. Both the premature fusion of cranial sutures and ossification delays of frontal bones may play a role in the prominent forehead observed in ACH patients. In addition, this excessive frontal convexity is also accentuated by the presence of a nasal root depression at the nasofrontal junction, associated with the restricted anteroposterior growth of the skull base. Obstructive sleep apnea in ACH can be related to multiple anomalies: volume reduction of the upper respiratory tract and nasopharyngeal stenosis (choanal stenosis, adenoids, and tonsils hypertrophy, as well as macroglossia), and airway muscles hypotonia 11 , 12 , 14 , 35 . Here we report two main age periods associated with higher values of AHI and OAHI, i.e 1–3 and 6–9 years, corresponding to the physiological higher incidence of adenoid and tonsils hypertrophy, respectively. Although an influence of nasopharyngeal obstructive factors in persisting obstructive sleep apnea has been reported in ACH, the surgical correction of these anomalies is often insufficient to correct apneas 11 , 43 . This is possibly because bony anomalies including a short skull base and a midfacial retrusion persist. However, a correlation between craniofacial skeletal shape modifications and severity of OSA had never been confirmed in children with ACH. Here, we report significant correlations between maxillo-mandibular anomalies and AHI, OAHI, and hypoxia: greater AHI and OAHI and lower SpO 2 min values were both associated with severe maxillary retrusion and retrognathism. In addition, higher AHI and OAHI significantly correlated with smaller C1-C2 angle values, highlighting correlation between skull base changes, maxillo-mandibular retrusion, and severity of obstructive sleep apnea. However, we cannot exclude structural and functional upper respiratory tract anomalies in ACH. Although it has been shown that FGFR2 activating mutations lead to abnormal tracheal formation and segmentation 44 – 46 , there is no data available documenting the impact of FGFR3 activating mutations on respiratory tract formation. Therefore, a potential intrinsic impact of FGFR3 mutations on airway formation, development, and function remains to be elucidated. In addition to premature fusion of skull base synchondroses leading to anteroposterior craniofacial growth limitation, reduction of the nasopharyngeal airway flow itself also contributes to impair transverse and sagittal facial growth, as observed in mouth-breather non-syndromic children presenting chronic nasal obstruction 47 . In this context, functional defects due to FGFR -related anatomical anomalies most probably add to the ongoing effects of the FGFR3 activating mutation in the aggravation of the phenotype with age. The presence of an anatomo-functional correlation between maxillo-mandibular retrusion and OSA in ACH objectively stresses the clinical need for a specialized multidisciplinary follow-up in this condition with systematic craniomaxillofacial and orthodontic evaluations. Although the benefit of maxillary expansion in releasing nasal obstruction remains unclear, this orthodontic treatment is often recommended to treat palatal transversal insufficiency in ACH after the age of 6. Maxillary advancement is sometimes required, using either controversial orthodontic appliances (Delaire type facemasks 48 ) in the less severe cases, or surgery, in the cases of a severe maxillary retrusion, morphological and functional defects (OSA, snoring). CPAP face masks may limit the feasibility of these treatments because of the external forces applied on the midface causing a deleterious effect during maxillary advancement. Development of new CPAP appliances minimizing pressure on the midface should thus be considered in ACH patients 49 . Prior to the present study, 2/15 patients benefited of maxillary expansion and/or maxillary protraction appliance (Delaire type facemasks 48 ). One of these patients underwent an interceptive Le Fort I osteotomy with distraction at the age of 10. Orthodontic treatment was also planned for five patients, and interceptive Le Fort I osteotomy with distraction was considered for two patients. Systematic re-assessment during growth was decided otherwise. Although our sample did not allow us to address this question, future studies should investigate the impact of orthodontic treatments and orthognathic surgery on OSA. These large multicentric and prospective cohorts are useful to understand whether and how additional potential factors (such as upper airway hypotonia or collapse, and macroglossia) could contribute to OSA in ACH. Conclusions This study highlighted that achondroplasia leads to different degrees of craniofacial morphological and functional severity. We showed for the first time, aggravation of craniofacial phenotype during growth, and an anatomofunctional correlation between the severity of maxillo-mandibular retrusion and OSA. Soon, FGFR -related conditions due to activating mutations may benefit from medical treatments that will hopefully reduce the need for invasive surgical procedures. In this context, precise knowledge on the natural history of these conditions including ACH is crucial for adapting future treatment and assessing their efficiency, especially in resolving functional anomalies like OSA. Abbreviations ACH: achondroplasia; CPAP: Continuous Positive Airway Pressure; FGFR: Fibroblast Growth; OSA: obstructive sleep apnea; AHI: Apnea Hypopnea Index; OAHI: Obstructive Apnea Hypopnea Index; SpO 2: pulse oximetry; PtcCO2: transcutaneous carbon dioxide pressure; ISS: intra-sphenoidal synchondrosis; SOS: spheno-occipital synchondrosis. Declarations Ethics approval and consent to participate The study was performed in accordance with the rules of local ethics committees (Comité d’Ethique Necker Enfants Malades). An informed consent to participate in the study was obtained from patient’s parents. Consent for publication A written informed consent for publication was obtained from patient’s parents prior to submission. Availability of data and materials All data generated or analysed during this study are included in this published article (and its supplementary information files). Competing interests The authors declare that they have no competing interests. Funding Not applicable. Authors’ contributions Anne Morice contributed to the conception, design of the study, acquisition, analyses, and data interpretation, and has drafted the work. Maxime Taverne contributed to the design of the study, the analyses and data interpretation and participated in the drafting of the work. Sophie Eche and Lucie Griffon contributed to data collection, acquisition and analyses. Nicolas Leboulanger, Vincent Couloigner, Geneviève Baujat, and Arnaud Picard contributed to the acquisition and interpretation of the data. Brigitte Fauroux contributed to the study design, the data interpretation, and to the revision of the work. Laurence Legeai-Mallet contributed to the data interpretation and the critical revision of the work. Natacha Kadlub contributed to the study design, the data collection and interpretation, and the critical revision of the work. Roman Hossein Khonsari contributed to the study design, data interpretation and the critical revision of the work. All coauthors have approved the submitted version and agreed both to be personally accountable for the author's own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature. Acknowledgements Special thanks to Necker - Enfants Malades hospital consultants who contributed to data collection: Pr. Valérie Cormier-Daire (medical genetics), Pr. Nathalie Boddaert (medical imaging), Dr Giovanna Paternoster (neurosurgery), and to Pr. Martin Biosse-Duplan (dentist, Bretonneau hospital, Paris). Anne Morice’s PhD position was supported by a ‘Poste d’Accueil’ grant from INSERM, France, and from an ‘Impulsion Recherche’ grant from the ‘Filière de Santé Maladies Rares TeteCou’. Maxime Taverne’s post-doctoral position was supported by a 2020 ‘Emergence’ grant from the ‘Mairie de Paris’. 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Supplementary Files SupplFig1.jpg Figure S1: Cephalometric studies according Delaire 17 : definition of landmarks, lines, and distances SupplTable1.jpg Table S1: Cephalometric studies according Delaire 17 : definition of landmarks, lines, and distances SupplTable2.jpg Table S2: 3D morphometric studies: anatomical skull and mandible landmarks. SupplTable3.png Table S3: Two-block partial least-square regressions (2bPLS) aiming at describing trends of covariation between skull and mandible shape and age, within patient or control groups. Last column displays the comparison of rPLS between the two groups (rPLS: coefficient of covariation, P: p-value, BOAS: aligned landmark coordinates before scaling, PROCRUSTES: aligned landmark coordinates after scaling). Bold values indicate p-values < 0.05. SupplTable4.png Table S4: Differences in Procrustes distances at each landmark between controls and patients. Theoretical shape information at 6 ages extracted from the axis of covariation given by the two-block partial least-square regressions between Procrustes coordinates of skulls or mandibles and age (in years, yo) within each group of subjects. SupplTable5.jpg Table S5: Characteristics of the patients: respiratory data and interventions SupplTable6.png Table S6: Respiratory polygraphy data of the 15 patients SupplTable7.jpg Table S7: Stepwise multiple regressions between sleep parameters and cephalometric parameters. Each model assessed one sleep study parameter (AHI, OAHI, % of time with PtcCO₂ > 50 mmHg, Maximal PtcCO₂ (mmHg), SpO 2 min, and oxygen desaturation index) versus all cephalometric parameters. The contributions of individual explanatory variables were estimated according to the slope of the correlation, the standardized coefficient (β coeff), the t-statistics, and the p-value of simple regressions (Pr). Statistically significant values are indicated in bold. adj-R²: adjusted Pearson’s determination coefficient. SupplTable8.jpg Table S8: Results of the non-parametric three-way multivariate analyses of variance (MANOVAs with permutation procedure) between sets of sleep and cephalometric parameters and the maxillo-zygomatic retrusion grade, sex and patient age. These include the effect of each explanatory variable individually and all possible interactions between them. Df: degree of freedom; R²: Pearson’s determination coefficient; F: F-statistic; Z: Z-scores; Pr: p-value associated with the F test. Bold values indicate significant results. SupplTable9.png Table S9: Univariate pairwise permutation tests between the maxillo-zygomatic retrusion grade (MZR) or sex (the two factors that multivariate permutation tests revealed to be significantly influencing cephalometrics, see Table S2) and each of the cephalometric variables. Cite Share Download PDF Status: Published Journal Publication published 18 Apr, 2023 Read the published version in Orphanet Journal of Rare Diseases → Version 1 posted Reviewers agreed at journal 26 May, 2022 Reviewers invited by journal 28 Apr, 2022 Editor assigned by journal 21 Apr, 2022 First submitted to journal 19 Apr, 2022 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-1574137","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":102202851,"identity":"ebe23e65-97a2-467b-8230-b3da185e599f","order_by":0,"name":"Anne 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moderate nasal bone hypoplasia (patient B), totally flattened nasal root with severe nasal bone hypoplasia (patient C), forehead: flattened (patient A), moderate convexity (patient B), markly prominent forehead (patient C).\u003c/p\u003e","description":"","filename":"Figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/ace39433d74fd609548ded12.jpg"},{"id":21123892,"identity":"fe77797d-32d3-4433-9ae0-e0520de9ac3a","added_by":"auto","created_at":"2022-05-05 16:46:49","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":84816,"visible":true,"origin":"","legend":"\u003cp\u003eAnatomical landmarks placed on the skull (frontal and lower views; midline sagittal section) and mandible (frontal and lateral views). Landmarks 13-22 on the mandible are not visible, since they are symmetrically placed on the left side of the mandible. Color code for the skull: face = blue; cranial vault = orange; skull base midline = grey. Color code for the mandible: mandibular corpus = blue; mandibular ramus = orange.\u003c/p\u003e","description":"","filename":"Figure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/7d88a7a18130f4cb0527436b.jpg"},{"id":21124551,"identity":"34609d99-f06c-437e-aba5-fba23b13e8bf","added_by":"auto","created_at":"2022-05-05 16:56:49","extension":"jpg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":415929,"visible":true,"origin":"","legend":"\u003cp\u003e2b-PLS regressions between skull morphology and age (3A), and between mandibular morphology and age (3B), describing growth trajectories in patients and controls, before (Boas coordinates) and after scaling (Procrustes coordinates). Numbers refer to age in years. Skull deformation series correspond to theoretical intermediate shapes along the covariation axis (negative values on the left side).\u003c/p\u003e","description":"","filename":"Figure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/decb3674a8a41f44d5ca070c.jpg"},{"id":21123889,"identity":"97b699ee-55f5-4095-8260-f220fc6e15b9","added_by":"auto","created_at":"2022-05-05 16:46:49","extension":"jpg","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":89385,"visible":true,"origin":"","legend":"\u003cp\u003ePatterns of phenotypic aggravation with age. Aggravation was defined as the increase of Procrustes distance for each landmark between controls and patients, by comparing the general growth trajectory of each group which was provided by the two-blocks partial least-squares regressions between Procrustes coordinates and age. Aggravation was averaged by anatomical region within both skull and mandible. In each graph, the x-axis was age in years (yo), and the y-axis was the Procrustes distance (no unit). The lower part of the figure represents theoretical morphological deformation of the skull (frontal and inferior views) and mandible (frontal and dorsal views) at 6 different ages (from 6 months to 12 years old), with landmarks highlighted in a gradient of color providing information about the intensity of the deformation in patients (Procrustes distance).\u003c/p\u003e","description":"","filename":"Figure4.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/5f2bebcf3ef8e110831f7c44.jpg"},{"id":21124277,"identity":"5970ebe5-d872-4ac0-8a2b-e92547e487c6","added_by":"auto","created_at":"2022-05-05 16:51:49","extension":"jpg","order_by":5,"title":"Figure 5","display":"","copyAsset":false,"role":"figure","size":283580,"visible":true,"origin":"","legend":"\u003cp\u003eAHI and OAHI before and after upper airway surgery, per age groups. Values obtained from patients who required non-invasive CPAP ventilation at the time of the sleep study are labeled (a unique symbol is used for each patient). AHI: apnea hypopnea index, OAHI: obstructive apnea hypopnea index.\u003c/p\u003e","description":"","filename":"Figure5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/a1b801ddf9d732f2805c8a9d.jpg"},{"id":44725971,"identity":"9230b79d-87d1-4314-a14f-7469abe36bb9","added_by":"auto","created_at":"2023-10-16 20:44:42","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":794375,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/83cf33a0-5715-4729-9bdd-20fba7ae304b.pdf"},{"id":21123896,"identity":"ee82a882-1856-4661-87c8-bacd203df5d3","added_by":"auto","created_at":"2022-05-05 16:46:49","extension":"jpg","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":375236,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eFigure S1\u003c/strong\u003e: Cephalometric studies according Delaire\u003csup\u003e17\u003c/sup\u003e: definition of landmarks, lines, and distances\u003c/p\u003e","description":"","filename":"SupplFig1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/407f4fbeb3509f2b305167ff.jpg"},{"id":21124275,"identity":"68c1f5c7-093a-493d-a3b6-ffcc5d1de6ce","added_by":"auto","created_at":"2022-05-05 16:51:49","extension":"jpg","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":520025,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S1\u003c/strong\u003e: Cephalometric studies according Delaire\u003csup\u003e17\u003c/sup\u003e: definition of landmarks, lines, and distances\u003c/p\u003e","description":"","filename":"SupplTable1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/9f7ad7b81fce3419c6eada2b.jpg"},{"id":21123898,"identity":"bacaab5f-065f-4a0b-894d-f72336eaae51","added_by":"auto","created_at":"2022-05-05 16:46:49","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":854524,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S2\u003c/strong\u003e: 3D morphometric studies: anatomical skull and mandible landmarks.\u003c/p\u003e","description":"","filename":"SupplTable2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/f6ac4ea921865c4293b450c5.jpg"},{"id":21123893,"identity":"ddf8a730-155a-4e58-a087-726a08ae58ad","added_by":"auto","created_at":"2022-05-05 16:46:49","extension":"png","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":40210,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S3\u003c/strong\u003e: Two-block partial least-square regressions (2bPLS) aiming at describing trends of covariation between skull and mandible shape and age, within patient or control groups. Last column displays the comparison of rPLS between the two groups (rPLS: coefficient of covariation, P: p-value, BOAS: aligned landmark coordinates before scaling, PROCRUSTES: aligned landmark coordinates after scaling). Bold values indicate p-values \u0026lt; 0.05.\u003c/p\u003e","description":"","filename":"SupplTable3.png","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/5f6d6c90cc5e9745b1333370.png"},{"id":21124276,"identity":"23276938-d03a-4883-ab8d-ed400fb33e96","added_by":"auto","created_at":"2022-05-05 16:51:49","extension":"png","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":225582,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S4\u003c/strong\u003e: Differences in Procrustes distances at each landmark between controls and patients. Theoretical shape information at 6 ages extracted from the axis of covariation given by the two-block partial least-square regressions between Procrustes coordinates of skulls or mandibles and age (in years, yo) within each group of subjects.\u003c/p\u003e","description":"","filename":"SupplTable4.png","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/9b34d406ca6aed4be7da54eb.png"},{"id":21123903,"identity":"d142c43a-2594-43bc-a054-57facaec8f2a","added_by":"auto","created_at":"2022-05-05 16:46:49","extension":"jpg","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":365812,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S5\u003c/strong\u003e:\u003cstrong\u003e \u003c/strong\u003eCharacteristics of the patients: respiratory data and interventions\u003c/p\u003e","description":"","filename":"SupplTable5.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/9dac255ddc68b86dc2f34cba.jpg"},{"id":21123900,"identity":"da521415-99af-4e07-a884-da789ca42502","added_by":"auto","created_at":"2022-05-05 16:46:49","extension":"png","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":168468,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S6\u003c/strong\u003e: Respiratory polygraphy data of the 15 patients\u003c/p\u003e","description":"","filename":"SupplTable6.png","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/c338db55a38e9fcce9b3be61.png"},{"id":21124278,"identity":"c43a5b96-ad3c-4008-a846-37b60ac143be","added_by":"auto","created_at":"2022-05-05 16:51:49","extension":"jpg","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":483803,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S7\u003c/strong\u003e: Stepwise multiple regressions between sleep parameters and cephalometric parameters. Each model assessed one sleep study parameter (AHI, OAHI, % of time with PtcCO₂ \u0026gt; 50 mmHg, Maximal PtcCO₂ (mmHg), SpO\u003csub\u003e2\u003c/sub\u003e min, and oxygen desaturation index) versus all cephalometric parameters. The contributions of individual explanatory variables were estimated according to the slope of the correlation, the standardized coefficient (β coeff), the t-statistics, and the p-value of simple regressions (Pr). Statistically significant values are indicated in bold. adj-R²: adjusted Pearson’s determination coefficient.\u003c/p\u003e","description":"","filename":"SupplTable7.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/75c4ddc1d3fecf3e99bffdd9.jpg"},{"id":21123902,"identity":"a3ee2a64-1565-4fd2-b20e-e7e0931036d9","added_by":"auto","created_at":"2022-05-05 16:46:49","extension":"jpg","order_by":9,"title":"","display":"","copyAsset":false,"role":"supplement","size":449451,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S8\u003c/strong\u003e: Results of the non-parametric three-way multivariate analyses of variance (MANOVAs with permutation procedure) between sets of sleep and cephalometric parameters and the maxillo-zygomatic retrusion grade, sex and patient age. These include the effect of each explanatory variable individually and all possible interactions between them. Df: degree of freedom; R²: Pearson’s determination coefficient; F: F-statistic; Z: Z-scores; Pr: p-value associated with the F test. Bold values indicate significant results.\u003c/p\u003e","description":"","filename":"SupplTable8.jpg","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/ec24fec9394e8e8efc7751c1.jpg"},{"id":21124280,"identity":"ecbf6a7d-3bca-4cb0-a572-ac550567b45a","added_by":"auto","created_at":"2022-05-05 16:51:49","extension":"png","order_by":10,"title":"","display":"","copyAsset":false,"role":"supplement","size":129618,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable S9\u003c/strong\u003e: Univariate pairwise permutation tests between the maxillo-zygomatic retrusion grade (MZR) or sex (the two factors that multivariate permutation tests revealed to be significantly influencing cephalometrics, see Table S2) and each of the cephalometric variables.\u003c/p\u003e","description":"","filename":"SupplTable9.png","url":"https://assets-eu.researchsquare.com/files/rs-1574137/v1/f0e13049c1372db1445d83ba.png"}],"financialInterests":"","formattedTitle":"Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients","fulltext":[{"header":"Background","content":"\u003cp\u003eAchondroplasia (ACH, OMIM 100800) is the most frequent form of chondrodysplasia, occurring with an incidence ranging from 1/30 000 to 1/10 000\u003csup\u003e1,2\u003c/sup\u003e. Clinical presentation is characterized by rhizomelic dwarfism and craniofacial anomalies, including macrocephaly, frontal bossing, midface retrusion, mandibular malformations, and cranio-vertebral junction anomalies\u003csup\u003e\u003cspan additionalcitationids=\"CR2 CR3\" citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eAchondroplasia is due to activating mutations in the Fibroblast Growth Factor Receptor 3 gene (\u003cem\u003eFGFR3\u003c/em\u003e), consisting in a glycine -to- arginine substitution in the transmembrane domain of the receptor (position 380) in more than 97% of cases\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Activating \u003cem\u003eFGFR3\u003c/em\u003e mutations lead to disorganisation of growth plate cartilage, premature fusion of the skull base synchondroses and impairment of the bone elongation\u003csup\u003e3,7\u0026minus;10\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eToday, the exact function of \u003cem\u003eFGFR3\u003c/em\u003e activating mutations on craniofacial skeletal phenotype and growth in ACH is not well understood. A better characterization of skull bone anomalies using 3D representation is needed to better understand the multiple craniofacial anomalies. In clinical practice, describing growth and form of the skull in ACH is crucial to evaluate the functional consequences of midfacial retrusion, mandibular malformations, to establish evidence-based treatment plans. Obstructive and central sleep apnea are among the most critical functional issues in ACH, affecting 60% of patients\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e, and have been related to a sagittal shortening of the cranial base and stenosis of the foramen magnum\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e\u003c/sup\u003e. This obstructive sleep apnea (OSA)\u003csup\u003e\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e is partially due to midfacial retrusion. Currently, the relationship between skeletal craniofacial shape and functional respiratory anomalies is not well understood. Deciphering the craniofacial morphology and its growth in patient with ACH could help assess the beneficial effects of promising medical treatments that are currently being developed to counteract the effects of activating \u003cem\u003eFGFR3\u003c/em\u003e mutations\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e,\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eThe aim of this study was to better characterise and quantify the skeletal craniofacial phenotype in a cohort of 15 ACH patients, using clinical evaluation, 2D cephalometrics and 3D geometric morphometrics. We also investigated the relationship between craniofacial shape and sleep study parameters, to understand whether craniofacial anomalies could be predictive of the severity of obstructive sleep apnea.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv class=\"Section2\" id=\"Sec3\"\u003e\n \u003ch2\u003ePatients\u003c/h2\u003e\n \u003cp\u003eAll ACH patients were initially managed in the National Reference Centres for Congenital Bone Diseases (Centre de R\u0026eacute;f\u0026eacute;rence Maladies Rares MOC) and for Cleft and Maxillofacial Malformations (Centre de R\u0026eacute;f\u0026eacute;rence Maladies Rares MAFACE), located within Necker hospital. This retrospective study included ACH patients from 2017 to 2021 with confirmed FGFR3 gain of function mutation. We analysed clinical and orthodontics evaluation and photographs, respiratory polygraphic (PG) results, lateral cephalograms, and craniofacial computed tomographic (CT) scans, being both performed before any skeletal craniofacial procedure. Patients whose ages at PG and at cephalograms were not similar (\u0026gt;\u0026thinsp;20% of difference), were excluded from the study.\u003c/p\u003e\n \u003cp\u003eTo account for facial characteristics and to screen for potential clinical predictive factors of OSA, we classified three morphological features - maxillo-zygomatic retrusion, deep nasal root, prominent forehead - into three grades of severity. Facial profile was classified into three types (convex, concave, or flat) (Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Occlusion was defined using the Angle classification\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec4\"\u003e\n \u003ch2\u003eControls\u003c/h2\u003e\n \u003cp\u003eControls were selected among age and gender-matched patients without any reported craniofacial anomalies. These patients underwent CT-scans for the assessment of benign craniofacial trauma or infections (lower jaw infections excluded).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec5\"\u003e\n \u003ch2\u003eCephalometric analysis\u003c/h2\u003e\n \u003cp\u003eCephalometric analysis was performed according to Delaire\u0026apos;s principles\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e17\u003c/span\u003e\u003c/sup\u003e, using lateral cephalograms, with the software \u003cem\u003eDELAIRE CEPHALOMETRIE\u003c/em\u003e (Blued\u0026apos;IS, B\u0026eacute;themont la For\u0026ecirc;t, France). Fourteen landmarks were manually placed on each lateral cephalogram, defining 12 lines. Cranial and facial cephalometric analyses are described in supplementary data section (Figure S1 and Table S1).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec6\"\u003e\n \u003ch2\u003eInvestigation of skull and mandible shape\u003c/h2\u003e\n \u003cp\u003eAn initial macroscopic analysis aimed at detecting potential premature fusion of skull vault sutures and skull base synchondroses, graded as follows: grade 1 (open), grade 2 (partially closed), and grade 3 (completely closed)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. Twenty landmarks were placed on the skull and twenty-three landmarks were placed on the mandible (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Table S2) using Avizo 2020 (Thermo Fisher Scientific). All computations and statistical analyses were performed using R\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e21\u003c/span\u003e\u003c/sup\u003e. Landmarks were aligned using Procrustes superimposition (\u003cem\u003eprocSym\u003c/em\u003e, \u003cem\u003eMorpho\u003c/em\u003e package)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e, either with (1) standardisation of overall size (generating Procrustes coordinates), and (2) without scaling (generating Boas coordinates). With and without scaling, the 3D coordinates of the aligned points were combined into matrices to perform subsequent multivariate statistical analyses. All following analyses that generated theoretical 3D shapes used the mandible and the skull of a control individual as the reference shape. This reference shape was obtained by segmenting the CT-scan images of the individual with Avizo and by exporting the constructed volumes as 3D surface objects. Growth trajectories within each group of subjects were estimated from two-blocks partial least-squares regressions (2b-PLS), using \u003cem\u003epls2B\u003c/em\u003e from the \u003cem\u003eMorpho\u003c/em\u003e package\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. The first block corresponded to the Procrustes or Boas coordinates, and the second block corresponded to the log10-transformed age in years. Theoretical morphological variations along the statistically significant axis of covariation between shape and age were displayed using \u003cem\u003etps3d\u003c/em\u003e (\u003cem\u003eMorpho\u003c/em\u003e package)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. Patterns of morphological changes during growth were compared between groups of individuals, first qualitatively, then quantitatively using the \u003cem\u003ecompare.pls\u003c/em\u003e (\u003cem\u003egeomorph\u003c/em\u003e package)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e23\u003c/span\u003e\u0026ndash;\u003cspan class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. The covariation axes of the 2b-PLS regressions of Procrustes coordinates relative to age were used to extract theoretical morphologies at 6 different ages in each group: 0.5, 1, 3, 6, 9 and 12 years of age. Procrustes distances were computed for each landmark between the theoretical shapes in the two groups of patients, to estimate possible aggravation, defined as the increase in morphological differences between controls and patients with age. Deformation was then averaged within subsets of landmarks corresponding to 5 anatomical regions (Fig. \u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e). For the skull, three areas were considered: the face (LM 1\u0026ndash;13), cranial vault (LM 14\u0026ndash;17), and skull base (LM 18\u0026ndash;20). For the mandible, we considered two areas: the mandibular ramus (LM 1\u0026ndash;5, 11\u0026ndash;19, 22) and mandibular corpus (the remaining landmarks). For each of these 5 anatomical regions, a logarithmic equation describing the evolution of deformation with age was generated. These growth equations enabled predicting deformation with age. The relationship between the intensity of morphological deformation and indices of apnea (see below, apnea-hypopnea index\u0026thinsp;=\u0026thinsp;AHI and obstructive AHI\u0026thinsp;=\u0026thinsp;OAHI) was investigated by computing stepwise regressions (using \u003cem\u003estepAIC\u003c/em\u003e from the \u003cem\u003eMASS\u003c/em\u003e package)\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e between AHI or OAHI and the deformation of the five previously defined anatomical areas.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec7\"\u003e\n \u003ch2\u003eSleep parameters\u003c/h2\u003e\n \u003cp\u003eOvernight PG with the recording of nasal flow, respiratory movements (bands), tracheal sound, body position, electrocardiogram, heart rate, pulse oximetry (SpO\u003csub\u003e2\u003c/sub\u003e), and transcutaneous carbon dioxide pressure (PtcCO2) were performed in room air (American Thoracic Society, 1996). Obstructive, central, mixed apnea and hypopnea were defined as previously described\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. The AHI was calculated as the sum of the apnea and hypopnea events per hour of total sleep. Sleep study was considered normal for AHI\u0026thinsp;\u0026lt;\u0026thinsp;1.5 /hour\u003csup\u003e27\u003c/sup\u003e. PtcCO\u003csub\u003e2\u003c/sub\u003e was recorded simultaneously by a Sentec monitor (Sentecr, Therwill, Switzerland). The oxygen desaturation index (ODI) was considered abnormal when \u0026gt;\u0026thinsp;5 /hour. All available PG from all patients were considered to evaluate the evolution of sleep apnea during growth and after airways surgery.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec8\"\u003e\n \u003ch2\u003eRelationships between cephalometric and sleep parameters\u003c/h2\u003e\n \u003cp\u003eThe correlation between each quantitative sleep parameter individually and all cephalometric variables was investigated through stepwise multiple regressions (using \u003cem\u003estep.AIC\u003c/em\u003e from the \u003cem\u003eMASS\u003c/em\u003e package. This enabled the best model to be retained by minimising the Akaike Information Criterion (AIC). Hence, the relative contributions of the explanatory variables to the variation of the dependent variable were assessed by computing the standardised (beta) coefficients.\u003c/p\u003e\n \u003cp\u003eNon-parametric three-way multivariate analyses of variance (MANOVAs with permutation procedure) enabled the estimation of the effects of the severity of maxillo-zygomatic retrusion, age and sex on the cephalometric and sleep parameters, using \u003cem\u003eprocD.lm\u003c/em\u003e from the \u003cem\u003egeomorph\u003c/em\u003e package. Univariate pairwise permutation tests (alternative to the parametric univariate analyses of variance - ANOVA - and to \u003cem\u003epost-hoc\u003c/em\u003e tests) were computed with \u003cem\u003epairwise PermutationTest\u003c/em\u003e from the \u003cem\u003ercompanion\u003c/em\u003e package\u003csup\u003e\u003cspan class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e. These analyses aimed to investigate the effect of the factors that had shown significant influence in earlier multivariate analyses on individual cephalometric variables separately, and to perform pairwise mean comparison. The procedure applied a Bonferroni adjustment of the \u003cem\u003ep-value\u003c/em\u003e to balance the biases of multiple comparisons.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv class=\"Section2\" id=\"Sec10\"\u003e\n \u003ch2\u003ePatients\u003c/h2\u003e\n \u003cp\u003eFifteen ACH patients were included. Mean age at initial clinical evaluation was 7.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.3 years; female / male ratio was 5/10. Genetic studies revealed the presence of a G380R mutation in \u003cem\u003eFGFR3\u003c/em\u003e gene in all tested patients (n\u0026thinsp;=\u0026thinsp;13). In the two remaining patients, born more than 15 years before the time of the study, molecular screening had not been performed, as genetic molecular confirmation was not mandatory at this period in these cases of typical clinical presentation of ACH. All patients presented a severe rhizomelic dwarfism, characterized by short limbs and trunk.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec11\"\u003e\n \u003ch2\u003eCraniofacial morphological multimodal assessment\u003c/h2\u003e\n \u003cdiv class=\"Section3\" id=\"Sec12\"\u003e\n \u003ch2\u003eClinical assessment\u003c/h2\u003e\n \u003cp\u003eFour patients presented i) mild, eight ii) moderate and three iii) severe maxillo-zygomatic retrusion (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e). Nasal root was deeply depressed in eleven patients and was less depressed in four patients. Forehead was flattened in 3/15, otherwise moderate convexity or marked prominent forehead affected 7/15 and 5/15 patients respectively. Profile was concave in 10/15, flat in 4/15, and convex in 1/15 patients.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec13\"\u003e\n \u003ch2\u003eCephalometric analysis\u003c/h2\u003e\n \u003cp\u003eMean age at cephalometric analysis was 7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2 years and was not statistically different from mean age at clinical evaluation. Maxillary retrusion and retrognathism, in relation to cranio-adapted F1, affected all patients (n\u0026thinsp;=\u0026thinsp;15). Skeletal Angle class was predominantly type III (n\u0026thinsp;=\u0026thinsp;10/15), and less frequently I or II (n\u0026thinsp;=\u0026thinsp;3 and 2/15, respectively). Gonial angle was mostly obtuse (n\u0026thinsp;=\u0026thinsp;13) (relative to F3/F7 angle) and acute in 2/15 patients. All patients had excessive vertical dimension of the lower third of the face. Cranial base angles were abnormal in all patients, the anterior angle being obtuse (\u0026gt;\u0026thinsp;22\u0026deg;) in 8/15 patients, and the posterior angle acute (\u0026lt;\u0026thinsp;115\u0026deg;) in 13/15 (Table\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e), accounting for modifications of the cranial base shape due to premature fusion of the skull base synchondroses (see below).\u003c/p\u003e\n \u003cdiv class=\"gridtable\"\u003e\n \u003ctable border=\"1\" id=\"Tab1\"\u003e\n \u003ccaption\u003e\n \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\n \u003cdiv class=\"CaptionContent\"\u003e\n \u003cp\u003eCephalometric analyses (n\u0026thinsp;=\u0026thinsp;15 patients). SD: standard deviation. For the definition of the cephalometric parameters (C1, F1, F1M, F1m, C2, C4), see Fig. \u003cspan class=\"InternalRef\"\u003e1\u003c/span\u003e/ Suppl Table\u0026nbsp;1.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eMean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eDefinition\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAge (years)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e7.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC1/F1 angle (degrees)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e87.8\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaxillo-mandibular position\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaxillary position C1/f1M angle (relative to F1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026minus;\u0026thinsp;10.3\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003emaxillary retrusion (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMandibular position (C1/f1m angle) (relative to F1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026minus;\u0026thinsp;8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eretrognathism (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMaxillo-mandibular discordance (f1M/1m angle)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026minus;\u0026thinsp;2.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eAngle class I/II/III (n\u0026thinsp;=\u0026thinsp;3/2/10)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eGonial angle (degrees)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e129.6\u0026thinsp;\u0026plusmn;\u0026thinsp;20.32\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eopen n\u0026thinsp;=\u0026thinsp;13, closed n\u0026thinsp;=\u0026thinsp;2 (relative to F3^F7 angle)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eVertical excess of the lower third of the face (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+\u0026thinsp;6\u0026thinsp;\u0026plusmn;\u0026thinsp;0.02\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003elower facial excess (n\u0026thinsp;=\u0026thinsp;15)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCranial base angles (degrees)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC1/C2 angle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e23.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.53\u003c/p\u003e\n \u003cp\u003e(20\u0026ndash;22)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eanterior angle of the cranial base (open n\u0026thinsp;=\u0026thinsp;8, closed n\u0026thinsp;=\u0026thinsp;5, normal n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eC1/C4 angle\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e111.2\u0026thinsp;\u0026plusmn;\u0026thinsp;11.3 (115\u0026ndash;120)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eposterior angle of the cranial base (open n\u0026thinsp;=\u0026thinsp;1, closed n\u0026thinsp;=\u0026thinsp;13, normal n\u0026thinsp;=\u0026thinsp;1)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n \u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec14\"\u003e\n \u003ch2\u003eCraniofacial shape and growth: 3D-CT assessment\u003c/h2\u003e\n \u003cdiv class=\"Section3\" id=\"Sec15\"\u003e\n \u003ch2\u003eCranial sutures and skull base synchondroses\u003c/h2\u003e\n \u003cp\u003eCraniofacial CT-scans were available for 11/15 patients (female/male ratio: 3/8), with a mean age of 4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.9 years (range 0,2\u0026ndash;13.6). Premature fusion of the squamo-sphenoidal suture affected 8/11 patients: either \u003cem\u003ein a partial\u003c/em\u003e or \u003cem\u003ecomplete form\u003c/em\u003e (4 patients each). A large anterior fontanelle was observed in 5/11 patients (all aged under 2 years), and 2/11 patients presented a mild fontanelle closure delay (ages 2.6 and 2.8 years).\u003c/p\u003e\n \u003cp\u003eAll 11/15 patients presented with premature fusions (1) of the intra-sphenoidal synchondrosis (ISS) with 10/11 in a \u003cem\u003ecomplete\u003c/em\u003e form (grade 3) and in 1/11 a \u003cem\u003epartial\u003c/em\u003e form (grade 2); (2) of the spheno-occipital synchondrosis (SOS) with 9/11 in a \u003cem\u003ecomplete\u003c/em\u003e (grade 3) and 2/11 in a \u003cem\u003epartial\u003c/em\u003e form (grade 2), and (3) of the intra-occipital synchondrosis (IOS) bilaterally with 8/11 in a \u003cem\u003ecomplete\u003c/em\u003e form (grade 3) and 3/11 in a \u003cem\u003epartial\u003c/em\u003e form (grade 3). A \u003cem\u003ecomplete\u003c/em\u003e fusion of the spheno-ethmoidal synchondrosis (grade 3) was observed in 7/11 patients, though it remained open (grade 1) in 4/11 patients.\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec16\"\u003e\n \u003ch2\u003eGrowth trajectories\u003c/h2\u003e\n \u003cp\u003eBoth standardized (Procrustes coordinates) and non-standardized (Boas coordinates) skull and mandible shapes strongly covaried (rPLS\u0026thinsp;\u0026gt;\u0026thinsp;0.9) with age within the ACH group and the control group (Table S3, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e). The strength of the covariation, provided by the rPLS index, was never significantly different between the two groups of patients, suggesting that intra-group variability in phenotype relative to age was comparable in the two cohorts.\u003c/p\u003e\n \u003cp\u003eThe 2b-PLS regressions between Boas coordinates of the skull and age showed that, compared with controls, the growth of the skull in ACH was characterized by an overall retrusion of the midface and a forward tilting of the anterior aspect of the skull base, leading to a tightening of the space between skull base and the posterior part of the maxilla (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e).\u003c/p\u003e\n \u003cp\u003eMore precisely, facial shape in ACH was characterised by a deep nasal root and a maxillo-zygomatic retrusion. The angulation of the skull base at the site of the SOS (with subsequent forward and downward tilting of the basisphenoid) and reduction of the skull base antero-posterior dimensions were associated with a shortening of the skull length. The orbits were vertically more elongated than in the control group. The skull vault became higher with age in the frontal region (which is mostly described by cephalometric landmark FPmid (Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and Table S2), compared with controls. Growth anomalies were also highlighted by 2b-PLS regressions between Procrustes skull coordinates and age, suggesting that these were not only due to size, but rather corresponded to disease-specific phenomena.\u003c/p\u003e\n \u003cp\u003eThe 2b-PLS regressions between Boas coordinates of the mandible and age showed that mandible growth in ACH was characterized by a backwards shift of the symphysis and greater symphysis height (defined as the distance between cephalometric landmarks 8 Pog and InfDe, see Figs.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, \u003cspan class=\"InternalRef\"\u003e3\u003c/span\u003e and Table S2). Additionally, the mandibular ramus became narrower and more vertical overall, the notch of the sigmoid was more profound, the coronoid process and the condyle were more vertically positioned, and the segment between the retromolar region and the mandibular ramus was more concave. A decrease in the overall antero-posterior length of the mandible seemed to occur before teenage years, characterized by the shortening and verticalization of the condyle in older ACH patients. This decrease in length did not seem to occur in the first years of life. Similar results were obtained after scaling, suggesting that size moderately affected these morphological variations.\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec17\"\u003e\n \u003ch2\u003ePhenotypic aggravation with age\u003c/h2\u003e\n \u003cp\u003eSkull vault showed the highest level of deformation between controls and patients (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Skull height increase was one of the main features of ACH. Nevertheless, the skull base and the face showed the most significant levels of aggravation with age (approximately\u0026thinsp;+\u0026thinsp;75% to +\u0026thinsp;106% of phenotypic deformation from 6 months to 12 years old, respectively) (Table S4). The facial landmarks that showed the greatest aggravation with age were those surrounding the nostrils (InfExOL, InfNasApR, InfNasApL, InfNasMid, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e, Table S4).\u003c/p\u003e\n \u003cp\u003eBoth the mandibular ramus and corpus showed comparable levels of phenotypic deformation between controls and patients. The most pronounced levels of aggravation were in the mandibular corpus (+\u0026thinsp;119% of phenotypic deformation). When considering landmarks separately and not by anatomical region, it appeared that not all landmarks showed the same levels of aggravation with age. Overall, disparity in the levels of aggravation among landmarks increased with age (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e4\u003c/span\u003e). Within the mandibular ramus, the areas experiencing the greatest deformation were the coronoid process, the condyle and the gonion (CorR, CoExtR, GoR, CorL, CoExtL, GoL); and within the mandibular corpus, the most inferior part of the chin (MeR, MeL, Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e2\u003c/span\u003e and Table S4).\u003c/p\u003e\n \u003cp\u003eNo significant model was retained from the stepwise regressions between the intensity of shape deformation and indices of apnea (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05).\u003c/p\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec18\"\u003e\n \u003ch2\u003eFunctional assessment: obstructive sleep apnea syndrome\u003c/h2\u003e\n \u003cdiv class=\"Section3\" id=\"Sec19\"\u003e\n \u003ch2\u003ePolygraphic results and upper airway surgery\u003c/h2\u003e\n \u003cp\u003eMean age at sleep study was 7.8\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2 years, which was not statistically different from mean age at cephalometric study (difference 0,1491\u0026thinsp;\u0026plusmn;\u0026thinsp;1,198). Sleep anomalies affected 80% of patients, with 33% patients having severe obstructive sleep apnea syndrome (AHI\u0026thinsp;\u0026gt;\u0026thinsp;=\u0026thinsp;10 events/hour) (Tables S5 and S6). Abnormal desaturations were observed in 13/15 patients. Apneas were mostly obstructive; the median index of central apnea was 0 (range 0\u0026ndash;2.2). In our series, cranio-vertebral decompression had been performed in 4/15 patients with central apnea due to foramen magnum stenosis. In these cases, sleep analyses selected for the present study were performed after cranio-vertebral decompression.\u003c/p\u003e\n \u003cp\u003eFourteen out of 15 patients benefited from upper airways surgery, mostly adeno-tonsillectomy and turbinectomy (Table S5). One out of 15 patients with severe ventilation disorders of multiple origins (pulmonary hypoplasia, obstructive apnea and central apnea due to upper spinal cord compression) had a tracheostomy and a cranio-vertebral decompression at the age of one and was decannulated two weeks post-operatively. Six out of 15 patients benefited from non-invasive continuous positive airway pressure (CPAP) ventilation, starting at the mean age of 4.9\u0026thinsp;\u0026plusmn;\u0026thinsp;3.2 years, and CPAP had been stopped following a normal sleep study without CPAP in 3/6 of them (mean age 9\u0026thinsp;\u0026plusmn;\u0026thinsp;1.7 years). In average, higher values of AHI and OAHI were observed at the ages 1\u0026ndash;3 (19.5\u0026thinsp;\u0026plusmn;\u0026thinsp;42.1, 13.5\u0026thinsp;\u0026plusmn;\u0026thinsp;28.9 evens/hour, respectively) and 6\u0026ndash;9 years of age (19.1\u0026thinsp;\u0026plusmn;\u0026thinsp;42.2, 15.2\u0026thinsp;\u0026plusmn;\u0026thinsp;30.3 events/hour, respectively) than at other ages (Fig.\u0026nbsp;\u003cspan class=\"InternalRef\"\u003e5\u003c/span\u003e), although not significantly (p\u0026thinsp;=\u0026thinsp;0.9, Kruskal-Wallis\u0026rsquo;s test).\u003c/p\u003e\n \u003c/div\u003e\n\u003c/div\u003e\n\u003cdiv class=\"Section2\" id=\"Sec20\"\u003e\n \u003ch2\u003eCraniofacial phenotype and sleep disorders: anatomo-functional correlation\u003c/h2\u003e\n \u003cp\u003eStepwise regressions between each sleep parameter and the set of cephalometric variables retained three statistically significant models (Table S7). Greater AHI and OAHI values were both associated with more pronounced maxillary retrusion and retrognathism, and with smaller C1-C2 values. When maxillary and mandibular retrusion increased, SpO2 min decreased. Non-parametric MANOVAs with permutation detected no relationship between sleep study parameters and the severity of maxillo-zygomatic retrusion, sex, and age (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05, Table S8). Cephalometric parameters were influenced by the grade of maxillo-zygomatic retrusion (p\u0026thinsp;=\u0026thinsp;0.034; R\u0026sup2; = 0.157; F\u0026thinsp;=\u0026thinsp;2.538; Z\u0026thinsp;=\u0026thinsp;1.904) and sex (p\u0026thinsp;=\u0026thinsp;0.011; R\u0026sup2; = 0.178; F\u0026thinsp;=\u0026thinsp;2.874; Z\u0026thinsp;=\u0026thinsp;2.287). More specifically, the univariate pairwise permutation tests did not reveal any significant relationship between the severity of maxillo-zygomatic retrusion and cephalometric parameters considered separately (Table S9). However, levels of maxillary retrusion and values of C1-C4 angles differed between sexes, with boys presenting with more severe maxillary retrusion and lower C1-C4 angle values than girls.\u003c/p\u003e\n\u003c/div\u003e"},{"header":"Discussion","content":"\u003cp\u003e \u003cem\u003eFGFR3\u003c/em\u003e is involved in craniofacial membranous and endochondral ossification processes\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. Gain-of-function \u003cem\u003eFGFR3\u003c/em\u003e mutations lead to dwarfism (ACH, hypochondroplasia, and thanatophoric dysplasia)\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e,\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e but also craniofacial suture fusions (craniosynostoses: Muenke syndrome and Crouzon syndrome with \u003cem\u003eacanthosis nigricans\u003c/em\u003e)\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e,\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eEven though all the ACH patients reported here presented typical craniofacial features (frontal bossing, macrocephaly, maxillary retrusion, deep nasal root, and prognathism)\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e,\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e\u003c/sup\u003e, we observed three grades of facial phenotype severity \u0026ndash; \u0026lsquo;mild\u0026rsquo;, \u0026lsquo;moderate\u0026rsquo; or \u0026lsquo;severe\u0026rsquo; \u0026ndash;, suggesting a phenotypic disparity in a genetic disease due in \u0026gt;\u0026thinsp;95% to a same G380R \u003cem\u003eFGFR3\u003c/em\u003e mutation. All patients presented a maxilla and mandible retrusion, an opening of gonial angle, a closure of the posterior skull base angles and a vertically elongated chin, confirming previous findings in ACH\u003csup\u003e\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eOur 3D morphometric analyses suggested an aggravation of the craniofacial phenotype with age. The most affected craniofacial region was the midface, characterised by an increased maxillary retrusion and a deeper nasal root with age. Aggravation of midface retrusion is most probably related to the premature fusion of skull base synchondroses consequently to activating \u003cem\u003eFGFR3\u003c/em\u003e mutations that impair cartilage homeostasis\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e, as observed in ACH mouse models. Normal synchondrosis fusion in humans follows a specific age-related sequence: ISS before the age of 2, IOS before the age of 7, spheno-ethmoidal synchondrosis before the age of 9, and SOS before puberty\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e,\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e\u003c/sup\u003e. Premature fusion of skull base synchondroses was always observed in our series, at the site of ISS, SOS and IOS. Gradual premature fusion of skull base synchondroses contributes to anteroposterior facial growth restriction and subsequent maxillary and midfacial retrusion\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e,\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e,\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e. In our series, we observed abnormal angulations at the site of the SOS. These skull angle modifications may be related to the premature fusion of the skull base synchondroses, but we cannot exclude the influence of intrinsic brain anomalies, especially of the temporal region, as already reported in \u003cem\u003eFGFR\u003c/em\u003e mutations\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e,\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e\u003c/sup\u003e. In addition, shape changes of the foramen magnum may also be involved in skull base anomalies, with secondary repercussions on the midface\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e,\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePremature fusion of skull vault sutures was observed in 80% of the patients at the squamo-sphenoidal suture, and all patients under the age of 2 had a large anterior fontanelle, indicating potential anomalies in the membranous ossification of the skull vault\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. In addition, brain anomalies and subsequent intracranial hypertension may also worsen skull shape deformations, fontanelle closure delay and frontal bone ossification delay. However, previous \u003cem\u003eex vivo\u003c/em\u003e studies conducted on a mouse model of ACH, \u003cem\u003eFgfr3\u003c/em\u003e\u003csup\u003e\u003cem\u003eY367Y/+\u003c/em\u003e\u003c/sup\u003e, showed that the ossification delay of skull vault occurred independently of the brain and cranial base, suggesting an intrinsic influence of \u003cem\u003eFGFR3\u003c/em\u003e gain-of-function mutations on membranous ossification\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e. Premature synostosis of one cranial suture constrains cranial growth at the site of the suture, and continuous growth of the underlying brain induces compensatory skull vault growth at the site of other non-fused cranial sutures, leading to skull deformations. Both the premature fusion of cranial sutures and ossification delays of frontal bones may play a role in the prominent forehead observed in ACH patients. In addition, this excessive frontal convexity is also accentuated by the presence of a nasal root depression at the nasofrontal junction, associated with the restricted anteroposterior growth of the skull base.\u003c/p\u003e \u003cp\u003eObstructive sleep apnea in ACH can be related to multiple anomalies: volume reduction of the upper respiratory tract and nasopharyngeal stenosis (choanal stenosis, adenoids, and tonsils hypertrophy, as well as macroglossia), and airway muscles hypotonia\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e,\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e\u003c/sup\u003e. Here we report two main age periods associated with higher values of AHI and OAHI, i.e 1\u0026ndash;3 and 6\u0026ndash;9 years, corresponding to the physiological higher incidence of adenoid and tonsils hypertrophy, respectively. Although an influence of nasopharyngeal obstructive factors in persisting obstructive sleep apnea has been reported in ACH, the surgical correction of these anomalies is often insufficient to correct apneas\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e\u003c/sup\u003e. This is possibly because bony anomalies including a short skull base and a midfacial retrusion persist. However, a correlation between craniofacial skeletal shape modifications and severity of OSA had never been confirmed in children with ACH. Here, we report significant correlations between maxillo-mandibular anomalies and AHI, OAHI, and hypoxia: greater AHI and OAHI and lower SpO\u003csub\u003e2\u003c/sub\u003e min values were both associated with severe maxillary retrusion and retrognathism. In addition, higher AHI and OAHI significantly correlated with smaller C1-C2 angle values, highlighting correlation between skull base changes, maxillo-mandibular retrusion, and severity of obstructive sleep apnea. However, we cannot exclude structural and functional upper respiratory tract anomalies in ACH. Although it has been shown that \u003cem\u003eFGFR2\u003c/em\u003e activating mutations lead to abnormal tracheal formation and segmentation\u003csup\u003e\u003cspan additionalcitationids=\"CR45\" citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR46\" class=\"CitationRef\"\u003e46\u003c/span\u003e\u003c/sup\u003e, there is no data available documenting the impact of \u003cem\u003eFGFR3\u003c/em\u003e activating mutations on respiratory tract formation. Therefore, a potential intrinsic impact of \u003cem\u003eFGFR3\u003c/em\u003e mutations on airway formation, development, and function remains to be elucidated.\u003c/p\u003e \u003cp\u003eIn addition to premature fusion of skull base synchondroses leading to anteroposterior craniofacial growth limitation, reduction of the nasopharyngeal airway flow itself also contributes to impair transverse and sagittal facial growth, as observed in mouth-breather non-syndromic children presenting chronic nasal obstruction\u003csup\u003e\u003cspan citationid=\"CR47\" class=\"CitationRef\"\u003e47\u003c/span\u003e\u003c/sup\u003e. In this context, functional defects due to \u003cem\u003eFGFR\u003c/em\u003e-related anatomical anomalies most probably add to the ongoing effects of the \u003cem\u003eFGFR3\u003c/em\u003e activating mutation in the aggravation of the phenotype with age.\u003c/p\u003e \u003cp\u003eThe presence of an anatomo-functional correlation between maxillo-mandibular retrusion and OSA in ACH objectively stresses the clinical need for a specialized multidisciplinary follow-up in this condition with systematic craniomaxillofacial and orthodontic evaluations. Although the benefit of maxillary expansion in releasing nasal obstruction remains unclear, this orthodontic treatment is often recommended to treat palatal transversal insufficiency in ACH after the age of 6. Maxillary advancement is sometimes required, using either controversial orthodontic appliances (Delaire type facemasks\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e) in the less severe cases, or surgery, in the cases of a severe maxillary retrusion, morphological and functional defects (OSA, snoring). CPAP face masks may limit the feasibility of these treatments because of the external forces applied on the midface causing a deleterious effect during maxillary advancement. Development of new CPAP appliances minimizing pressure on the midface should thus be considered in ACH patients\u003csup\u003e\u003cspan citationid=\"CR49\" class=\"CitationRef\"\u003e49\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003ePrior to the present study, 2/15 patients benefited of maxillary expansion and/or maxillary protraction appliance (Delaire type facemasks\u003csup\u003e\u003cspan citationid=\"CR48\" class=\"CitationRef\"\u003e48\u003c/span\u003e\u003c/sup\u003e). One of these patients underwent an interceptive Le Fort I osteotomy with distraction at the age of 10. Orthodontic treatment was also planned for five patients, and interceptive Le Fort I osteotomy with distraction was considered for two patients. Systematic re-assessment during growth was decided otherwise. Although our sample did not allow us to address this question, future studies should investigate the impact of orthodontic treatments and orthognathic surgery on OSA.\u003c/p\u003e \u003cp\u003eThese large multicentric and prospective cohorts are useful to understand whether and how additional potential factors (such as upper airway hypotonia or collapse, and macroglossia) could contribute to OSA in ACH.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThis study highlighted that achondroplasia leads to different degrees of craniofacial morphological and functional severity. We showed for the first time, aggravation of craniofacial phenotype during growth, and an anatomofunctional correlation between the severity of maxillo-mandibular retrusion and OSA.\u003c/p\u003e \u003cp\u003eSoon, \u003cem\u003eFGFR\u003c/em\u003e-related conditions due to activating mutations may benefit from medical treatments that will hopefully reduce the need for invasive surgical procedures. In this context, precise knowledge on the natural history of these conditions including ACH is crucial for adapting future treatment and assessing their efficiency, especially in resolving functional anomalies like OSA.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eACH: achondroplasia; CPAP: Continuous Positive Airway Pressure; FGFR: Fibroblast Growth; OSA: obstructive sleep apnea; AHI: Apnea Hypopnea Index; OAHI: Obstructive Apnea Hypopnea Index; SpO\u003csub\u003e2:\u0026nbsp;\u003c/sub\u003epulse oximetry; PtcCO2: transcutaneous carbon dioxide pressure; ISS: intra-sphenoidal synchondrosis; SOS: spheno-occipital synchondrosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study was performed in accordance with the rules of local ethics committees (Comit\u0026eacute; d\u0026rsquo;Ethique Necker Enfants Malades). An informed consent to participate in the study was obtained from patient\u0026rsquo;s parents.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA written informed consent for publication was obtained from patient\u0026rsquo;s parents prior to submission.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAll data generated or analysed during this study are included in this published article (and its supplementary information files).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnne Morice contributed to the conception, design of the study, acquisition, analyses, and data interpretation, and has drafted the work.\u003c/p\u003e\n\u003cp\u003eMaxime Taverne contributed to the design of the study, the analyses and data interpretation and participated in the drafting of the work.\u003c/p\u003e\n\u003cp\u003eSophie Eche and Lucie Griffon contributed to data collection, acquisition and analyses.\u003c/p\u003e\n\u003cp\u003eNicolas Leboulanger, Vincent Couloigner, Genevi\u0026egrave;ve Baujat, and Arnaud Picard contributed to the acquisition and interpretation of the data.\u003c/p\u003e\n\u003cp\u003eBrigitte Fauroux contributed to the study design, the data interpretation, and to the revision of the work.\u003c/p\u003e\n\u003cp\u003eLaurence Legeai-Mallet contributed to the data interpretation and the critical revision of the work.\u003c/p\u003e\n\u003cp\u003eNatacha Kadlub contributed to the study design, the data collection and interpretation, and the critical revision of the work.\u003c/p\u003e\n\u003cp\u003eRoman Hossein Khonsari contributed to the study design, data interpretation and the critical revision of the work.\u003c/p\u003e\n\u003cp\u003eAll coauthors have approved the submitted version and agreed both to be personally accountable for the author\u0026apos;s own contributions and to ensure that questions related to the accuracy or integrity of any part of the work, even ones in which the author was not personally involved, are appropriately investigated, resolved, and the resolution documented in the literature.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eSpecial thanks to Necker - Enfants Malades hospital consultants who contributed to data collection: Pr. Val\u0026eacute;rie Cormier-Daire (medical genetics), Pr. Nathalie Boddaert (medical imaging), Dr Giovanna Paternoster (neurosurgery), and to Pr. Martin Biosse-Duplan (dentist, Bretonneau hospital, Paris).\u003c/p\u003e\n\u003cp\u003eAnne Morice\u0026rsquo;s PhD position was supported by a \u0026lsquo;Poste d\u0026rsquo;Accueil\u0026rsquo; grant from INSERM, France, and from an \u0026lsquo;Impulsion Recherche\u0026rsquo; grant from the \u0026lsquo;Fili\u0026egrave;re de Sant\u0026eacute; Maladies Rares TeteCou\u0026rsquo;.\u003c/p\u003e\n\u003cp\u003eMaxime Taverne\u0026rsquo;s post-doctoral position was supported by a 2020 \u0026lsquo;Emergence\u0026rsquo; grant from the \u0026lsquo;Mairie de Paris\u0026rsquo;.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003e\u003cspan\u003eHorton WA, Hall JG, Hecht JT. Achondroplasia. 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PMID: 32656168; PMCID: PMC7322995.\u003c/span\u003e\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":true,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Achondroplasia, FGFR3, sleep apnoea, geometric morphometrics, cephalometrics, principal component analysis, craniofacial growth","lastPublishedDoi":"10.21203/rs.3.rs-1574137/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-1574137/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cem\u003eBackground\u003c/em\u003e\u003c/p\u003e\u003cp\u003eAchondroplasia is the most frequent FGFR3-related chondrodysplasia, leading to rhizomelic dwarfism, craniofacial anomalies, stenosis of the foramen magnum, and sleep apnea. Craniofacial growth and its correlation with obstructive sleep apnea syndrome has not been assessed in achondroplasia. In this study, we provide a multimodal analysis of craniofacial growth and anatomo-functional correlations between craniofacial features and the severity of obstructive sleep apnea syndrome.\u003c/p\u003e\u003cp\u003e\u003cem\u003eMethods \u003c/em\u003e\u003c/p\u003e\u003cp\u003eA multimodal study was performed based on a paediatric cohort of 15 achondroplasia patients, including clinical and sleep study data, 2D cephalometrics, and 3D geometric morphometry analyses.\u003c/p\u003e\u003cp\u003e\u003cem\u003eResults\u003c/em\u003e\u003c/p\u003e\u003cp\u003eCraniofacial phenotype was characterized by maxillo-zygomatic retrusion, deep nasal root, and prominent forehead. 2D cephalometric studies showed constant maxillo-mandibular retrusion, with excessive vertical dimensions of the lower third of the face, and modifications of cranial base angles. All patients with available CT-scan had premature fusion of skull base synchondroses. 3D morphometric analyses showed an aggravation of the craniofacial phenotype with age, predominantly affecting the midface - with increasing maxillary retrusion with age - as well as the skull base - with closure of the spheno-occipital angle. At mandibular level, both mandibular corpus and ramus showed significant levels of shape modifications with age, the highest level concerned the mandibular corpus (+119%). Anatomo-functional studies revealed significant correlation between the severity of maxillo-mandibular retrusion and obstructive sleep apnea syndrome (p\u0026lt;0.01).\u0026nbsp;\u003c/p\u003e\u003cp\u003e\u003cem\u003eConclusions\u003c/em\u003e\u003c/p\u003e\u003cp\u003eOur study provides new insights on the impact of FGFR3 activating mutations on craniofacial growth, and highlights anatomo-functional correlation between the severity of craniofacial features and obstructive sleep apnea syndrome.\u003cem\u003e \u003c/em\u003e\u003c/p\u003e","manuscriptTitle":"Craniofacial growth and function in achondroplasia: a multimodal 3D study on 15 patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2022-05-05 16:46:47","doi":"10.21203/rs.3.rs-1574137/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"","date":"2022-05-26T04:16:44+00:00","index":0,"fulltext":""},{"type":"reviewersInvited","content":"","date":"2022-04-28T16:11:12+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2022-04-21T16:29:33+00:00","index":"","fulltext":""},{"type":"submitted","content":"Orphanet Journal of Rare Diseases","date":"2022-04-19T16:16:03+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"orphanet-journal-of-rare-diseases","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"ojrd","sideBox":"Learn more about [Orphanet Journal of Rare Diseases](http://ojrd.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/ojrd/default.aspx","title":"Orphanet Journal of Rare Diseases","twitterHandle":"@bmc","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"BMC/SO AJ","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"125c0d4f-93a7-4394-9142-d0eeb7f31fe5","owner":[],"postedDate":"May 5th, 2022","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2023-10-16T20:38:52+00:00","versionOfRecord":{"articleIdentity":"rs-1574137","link":"https://doi.org/10.1186/s13023-023-02664-y","journal":{"identity":"orphanet-journal-of-rare-diseases","isVorOnly":false,"title":"Orphanet Journal of Rare Diseases"},"publishedOn":"2023-04-18 20:31:21","publishedOnDateReadable":"April 18th, 2023"},"versionCreatedAt":"2022-05-05 16:46:47","video":"","vorDoi":"10.1186/s13023-023-02664-y","vorDoiUrl":"https://doi.org/10.1186/s13023-023-02664-y","workflowStages":[]},"version":"v1","identity":"rs-1574137","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-1574137","identity":"rs-1574137","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}